Hepatocyte growth factor (HGF) promotes cell proliferation, migration, angiogenesis, survival and morphogenesis by activating the receptor tyrosine kinase Met (reviewed in 8, 9). In addition to its importance in normal physiology, the HGF/Met pathway has been implicated in invasive tumor growth and tumor metastasis (8). HGF has high similarity to the serine protease plasminogen and is composed of a α-chain containing an N-domain and four Kringle domains and a β-chain with homology to chymotrypsin-like proteases. It is secreted into the extracellular matrix as an inactive single chain precursor (pro-HGF) and requires activation cleavage at Arg494-Val495 to form the biologically competent, disulfide-linked α/β heterodimer (10-13). This step is mediated by pro-HGF converting serine proteases, such as hepatocyte growth factor activator (HGFA) (14). HGFA is inhibited by cell surface-expressed Kunitz-type inhibitors, such as the two hepatocyte growth factor activator inhibitor splice variants HAI-1 (16-17) and HAI-1B (15) and by HAI-2 (18). HAI-2 (also known as placental bikunin) (19) also potently inhibits factor XIa and plasma kallikrein (20), whereas HAI-1B has little or no inhibitory activity (15). Therefore, the biological availability of the pro-HGF pool in the extracellular matrix is regulated by the activities of pro-HGF convertases such as HGFA and their inhibitors.
Since activation of pro-HGF requires cleavage by a convertase such as HGFA, modulation of HGFA function and/or its interaction with its substrate could prove to be an efficacious therapeutic approach. In this regard, there is a clear need to identify clinically relevant agents capable of modulating activity of and/or specificifically interacting with HGFA. The invention fulfills this need and provides other benefits.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.